The human cortex is distinguished from other species by its size, addition of specialized cytoarchitectonic areas, new subtypes of neurons and increased number of connections that subserve unique functions such as language and higher order cognition. The mechanism by which human cortical distinction emerges during development and how it has evolved during evolution is not known. The evolutionary novelties in the cortex are likely to be an outcome of relatively small genetic differences effecting the timing, sequence and level of gene expression at early embryonic stages that can be uncovered only by studying unique features of cortical formation in human and non-human primates in comparison to rodent and other species. Genes, transcription factors and cellular mechanisms that generate species-specific differences and human distinction in cortical development have not been previously analyzed and we are in the unique position to address this biomedically significant, but neglected issue in modern neuroscience. The human telencephalic primordium can be distinguished from that of the mouse and monkey by its size, morphology, neural stem cell types, and hitherto unrecognized abventricular stem cells two weeks before the onset of neurogenesis from the local proliferative ventricular zone. Thus, we will focus on the initial stages of cortical development in the rodent (mouse), non-human primate (macaque) and human telencephalon by using the most advanced genetic molecular and in vitro and in vivo cell biological methods available. More specifically, we will perform: 1) Isolation, in vivo lineage analysis and histochemical characterization, fate determination and testing function and potential of the early ventricular, subventricular and abventricular neuronal stem cells in these three species; 2) Identification of genes differentially regulated among human, macaque and mouse early stem cell types using high throughput microarray gene expression analysis and in situ hybridization analysis of putatively differentially regulated genes; and, 3) Functional studies of genes screened in Specific Aim 1 & 2. Abnormal genesis and initial patterning of the human cerebral cortex can give rise to uniquely human neuropsychiatric disorders such as schizophrenia, autism, developmental dyslexia, mental retardation and response to drugs for therapy and abuse. PUBLIC HEALTH RELEVANCE: The proposed research focuses on the initial steps of cellular and molecular events that establish anatomical and functional differences between the embryonic human, non-human primates and rodent cerebral cortex. The expected set of unique data on the origin and nature of species-specific differences are not only of theoretical, but also of considerable clinical significance, as many of the newly evolved traits may be more vulnerable to genetic and environmental factors that can initiate certain human-specific neuropsychiatric disorders such as schizophrenia, autism, developmental dyslexia, mental retardation and response to drugs used in therapy and abuse.